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1.
JAMA Netw Open ; 7(3): e241155, 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38441899

RESUMO

This secondary analysis of a randomized clinical trial evaluates the effectiveness of ergocalciferol vs placebo in youths with newly diagnosed type 1 diabetes.


Assuntos
Diabetes Mellitus Tipo 1 , Ergocalciferóis , Humanos , Diabetes Mellitus Tipo 1/tratamento farmacológico
2.
BMC Pharmacol Toxicol ; 25(1): 19, 2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38395972

RESUMO

BACKGROUND: Previous studies investigating the effect of oral supplementation of paricalcitol on reactive protein levels in chronic kidney disease (CKD) patients reported inconsistent findings. In this systematic review and meta-analysis, we have analyzed and interpreted the results obtained from previous randomized clinical trials on the effect of paricalcitol on C-reactive protein in CKD patients in the literature. METHODS: MEDLINE, SciVerse Scopus, and Clarivate Analytics Web of Science databases were searched until January 2023 and related articles were obtained through a careful screening process allowing extraction of required data from selected articles. The effect size was calculated using a random effect model and weighted mean differences (WMD) and 95% confidence intervals (CI). Heterogeneity among studies was evaluated using Cochran's Q test and I2. RESULTS: Amongst the 182 articles obtained from the initial search, 4 studies (6 arms) were finally included in the meta-analysis. Pooled analysis shows that C-reactive protein levels significantly decrease after oral supplementation with paricalcitol (WMD: -2.55 mg/L, 95% CI (-4.99 to -0.11; P = 0.04). The studies used in this meta-analysis showed significant heterogeneity (I2 = 66.3% and P = 0.01). CONCLUSION: Oral paricalcitol supplementation in CKD patients can significantly reduce C-reactive protein levels, which may prevent CKD progression.


Assuntos
Proteína C-Reativa , Ergocalciferóis , Insuficiência Renal Crônica , Humanos , Proteína C-Reativa/análise , Suplementos Nutricionais , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Renal Crônica/tratamento farmacológico
3.
Sci Rep ; 14(1): 4866, 2024 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-38418932

RESUMO

There is no established treatment for progressive IgA nephropathy refractory to steroids and immunosuppressant drugs (r-IgAN). Interleukin 17 (IL-17) blockade has garnered interest in immune-mediated diseases involving the gut-kidney axis. However, single IL-17A inhibition induced paradoxical effects in patients with Crohn's disease and some cases of de novo glomerulonephritis, possibly due to the complete Th1 cell response, along with the concomitant downregulation of regulatory T cells (Tregs). Seven r-IgAN patients were treated with at least six months of oral paricalcitol, followed by the addition of subcutaneous anti-IL-17A (secukinumab). After a mean follow-up of 28 months, proteinuria decreased by 71% (95% CI: 56-87), P < 0.001. One patient started dialysis, while the annual eGFR decline in the remaining patients [mean (95% CI)] was reduced by 4.9 mL/min/1.73 m2 (95% CI: 0.1-9.7), P = 0.046. Circulating Th1, Th17, and Treg cells remained stable, but Th2 cells decreased, modifying the Th1/Th2 ratio. Intriguingly, accumulation of circulating Th17.1 cells was observed. This novel sequential therapy appears to optimize renal advantages in patients with r-IgAN and elicit alterations in potentially pathogenic T helper cells.


Assuntos
Ergocalciferóis , Glomerulonefrite por IGA , Humanos , Glomerulonefrite por IGA/tratamento farmacológico , Glomerulonefrite por IGA/patologia , Interleucina-17 , Diálise Renal , Células Th17/patologia
4.
BMJ Case Rep ; 17(2)2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38320825

RESUMO

Hypercalcaemia of malignancy (HCM) is a paraneoplastic syndrome that often portends a poor prognosis. We present an extremely rare (<1%) case of HCM due to extrarenal calcitriol (1,25-(OH)2D) production in a patient with splenic marginal zone lymphoma. A man in his 80s presented with a 3-week history of fatigue, unsteadiness and abdominal pain, and new findings of anaemia, kidney injury and hypercalcaemia. Laboratory evaluation, bone marrow biopsy and positron emission tomography/computed tomography (PET/CT) confirmed the diagnosis of splenic marginal zone lymphoma which produced calcitriol (1,25-(OH)2D3), causing the patient's hypercalcaemia.


Assuntos
Hipercalcemia , Síndromes Paraneoplásicas , Vitamina D , Humanos , Masculino , Calcitriol/biossíntese , Ergocalciferóis , Hipercalcemia/etiologia , Hipercalcemia/diagnóstico , Linfoma/complicações , Linfoma/diagnóstico , Síndromes Paraneoplásicas/complicações , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Vitamina D/efeitos adversos , Idoso de 80 Anos ou mais
5.
Adv Nutr ; 15(1): 100133, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37865222

RESUMO

BACKGROUND: Two previous meta-analyses showed smaller differences between vitamin D3 and vitamin D2 in raising serum 25-hydroxyvitamin D [25(OH)D] and a consistently high heterogeneity when only including daily dosing studies. OBJECTIVE: This study aimed to compare more frequently dosed vitamin D2 and vitamin D3 in improving total 25(OH)D and determine the concomitant effect of response modifiers on heterogeneity, and secondly, to compare the vitamin D2-associated change in 25(OH)D2 with the vitamin D3-associated change in 25(OH)D3. METHODS: PubMed, EMBASE, Cochrane, and the Web of Science Core collection were searched for randomized controlled trials of vitamin D2 compared with vitamin D3, daily or once/twice weekly dosed. After screening for eligibility, relevant data were extracted for meta-analyses to determine the standardized mean difference when different methods of 25(OH)D analyses were used. Otherwise, the weighted mean difference (WMD) was determined. RESULTS: Overall, the results based on 20 comparative studies showed vitamin D3 to be superior to vitamin D2 in raising total 25(OH)D concentrations, but vitamin D2 and vitamin D3 had a similar positive impact on their corresponding 25(OH)D hydroxylated forms. The WMD in change in total 25(OH)D based on 12 daily dosed vitamin D2-vitamin D3 comparisons, analyzed using liquid chromatography-tandem mass spectrometry, was 10.39 nmol/L (40%) lower for the vitamin D2 group compared with the vitamin D3 group (95% confidence interval: -14.62, -6.16; I2 = 64%; P < 00001). Body mass index (BMI) appeared to be the strongest response modifier, reducing heterogeneity to 0% in both subgroups. The vitamin D2- and vitamin D3-induced change in total 25(OH)D lost significance predominantly in subjects with a BMI >25 kg/m2 (P = 0.99). However, information on BMI was only available in 13/17 daily dosed comparisons. CONCLUSIONS: Vitamin D3 leads to a greater increase of 25(OH)D than vitamin D2, even if limited to daily dose studies, but vitamin D2 and vitamin D3 had similar positive impacts on their corresponding 25(OH)D hydroxylated forms. Next to baseline 25(OH)D concentration, BMI should be considered when comparing the effect of daily vitamin D2 and vitamin D3 supplementation on total 25(OH)D concentration. This study was registered in PROSPERO as CRD42021272674.


Assuntos
Colecalciferol , Deficiência de Vitamina D , Humanos , Colecalciferol/farmacologia , Ergocalciferóis , Índice de Massa Corporal , Suplementos Nutricionais , Vitamina D
6.
J Clin Endocrinol Metab ; 109(2): e646-e656, 2024 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-37738423

RESUMO

CONTEXT: Canagliflozin has been reported to increase the risk of bone fracture-possibly mediated by decreasing 1,25-dihydroxyvitamin D (1,25(OH)2D) and increasing parathyroid hormone (PTH). OBJECTIVE: This work investigated whether baseline vitamin D (VitD) deficiency renders individuals vulnerable to this adverse effect and whether VitD3 supplementation is protective. METHODS: This community-based, outpatient study had a paired design comparing individual participants before and after VitD3 supplementation. Eleven VitD-deficient (25-hydroxyvitamin D [25(OH)D] ≤ 20 ng/mL) individuals were recruited from the Amish population in Lancaster, Pennsylvania. Participants underwent 2 canagliflozin challenge protocols (300 mg daily for 5 days): the first before and the second after VitD3 supplementation. In the VitD3 supplementation protocol, participants received VitD3 supplementation (50 000 IU once or twice a week depending on body mass index for 4-6 weeks) to achieve 25(OH)D of 30 ng/mL or greater. Two coprimary end points were identified: effects of VitD3 supplementation on canagliflozin-induced changes in 1,25(OH)2D and PTH. Secondary end points included effects of VitD3 supplementation on baseline levels of VitD metabolites and PTH. RESULTS: VitD3 supplementation increased mean 25(OH)D from 16.5 ± 1.6 to 44.3 ± 5.5 ng/mL (P = .0006) and 24,25-dihydroxyvitamin D (24,25(OH)2D) from 1.0 ± 0.1 to 4.3 ± 0.6 ng/mL (P = .0002). Mean 1,25(OH)2D and PTH were unchanged. VitD3 supplementation decreased the magnitude of canagliflozin-induced changes in 1,25(OH)2D (from -31.3%±4.7% to -9.3%±8.3%; P = .04) and PTH (from +36.2%±6.2% to +9.7%±3.7%; P = .005). CONCLUSION: VitD deficiency rendered individuals more vulnerable to adverse effects of canagliflozin on biomarkers associated with bone health. VitD3 supplementation was protective against canagliflozin's short-term adverse effects on 1,25(OH)2D and PTH.


Assuntos
Hormônio Paratireóideo , Deficiência de Vitamina D , Humanos , Canagliflozina/efeitos adversos , Vitamina D/metabolismo , Deficiência de Vitamina D/tratamento farmacológico , Vitaminas , Ergocalciferóis , Suplementos Nutricionais/efeitos adversos
7.
Food Chem ; 439: 138091, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38104441

RESUMO

A robust method for quantitation of total vitamin D2 and D4 in mushrooms by high performance liquid chromatography with UV detection (HPLC-UV) was developed to analyze mushrooms exposed to UV light. A two-step solid phase extraction (SPE) (silica, carbon black) removed chromatographic interferences typically resolved only with mass spectrometric detection (LC-MS) and allowed quantitation of all vitamin D and pre-D analytes. The vitamin and pre-vitamin forms of D2, D4 and D3 (internal standard), as well as other photoisomers and sterols were resolved. Results for six types of UV-exposed mushrooms were comparable to LC-MS. Screening of ten additional types of UV-exposed mushrooms without the IS confirmed lack of interference with the IS. The limit of quantification (µg/100 g fresh weight) was 0.4 for vitamin D and 0.9 for pre-vitamin D. Mushrooms do not have to be dried, and separatory funnels and large solvent volumes were also eliminated from sample preparation.


Assuntos
Agaricales , Agaricales/química , Cromatografia Líquida de Alta Pressão/métodos , Ergocalciferóis/análise , Raios Ultravioleta , Vitamina D/análise , Vitaminas/análise , Extração em Fase Sólida
8.
Int Immunopharmacol ; 127: 111357, 2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38104366

RESUMO

Prolonged or excessive ultraviolet (UV) exposure can lead to premature skin aging. Doxercalciferol (Dox), an analog of vitamin D2, is chiefly used to treat endocrine diseases, cardiovascular diseases, kidney diseases, etc. To date, research on Dox in alleviating photoaging and UV-induced inflammation is scarce. In this research, we evaluated the function of Dox in ultraviolet radiation B (UVB)-induced photoaging and explored the potential mechanism in human keratinocytes (Hacat) and BALB/c mice. First, we established a stable UVB-induced photoaging cell model. Then, we found that the senescence ß-galactosidase (SA-ß-Gal) positive rate, senescence-related protein (p16), aging-related genes (p21 and p53), senescence-associated secretory phenotype (SASP), inflammatory driving factors (IL-1ß and IL-6) and matrix metalloproteinases (MMPs) (MMP1 and MMP9) were upregulated in HaCaT cells after UVB irradiation. At the same time, the effect of UVB on the back skin of BALB/c mice showed a consistent trend. Dox effectively alleviated the aforementioned changes caused by UVB radiation. Mechanistically, we found that UVB activated mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signaling pathways, and Dox inhibited UVB-activated NF-κB and MAPK. Furthermore, Dox inhibited UVB-induced skin photoaging and damage in mice. In summary, Dox has been improved to inhibit photoaging, which may help to develop therapies to delay skin photoaging.


Assuntos
Envelhecimento da Pele , Humanos , Animais , Camundongos , Raios Ultravioleta/efeitos adversos , Células HaCaT , NF-kappa B/metabolismo , Pele , Ergocalciferóis/farmacologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Senescência Celular , Fibroblastos
9.
S Afr Fam Pract (2004) ; 65(1): e1-e6, 2023 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-37916701

RESUMO

Vitamin D is a fat-soluble molecule referring to the different isoforms, ergocalciferol (D2) and cholecalciferol (D3). Its physiological functions include increasing calcium serum concentrations. 25-hydroxyvitamin D3 (25(OH)D) (Calcifediol), a non-active, circulating instant precursor is seen as a pre-hormone. Studies have shown that a deficiency in calcifediol is related to chronic conditions such as cardiovascular, musculoskeletal, immune system, neurological, and anti-neoplastic functions. Vitamin D supplementation has shown its benefit as prophylaxis and treatment during the coronavirus disease 2019 (COVID-19) pandemic and an increase in the prescribing of vitamin D supplementation has been observed. The intention of this review article is to provide guidance on the recommended dosage regimen as a prophylactic measure during COVID-19 and its use as a supplement in general. From this review article, it is clear that vitamin D has an important role to play not only in COVID-19 but also in various other health aspects of the human body.Contribution: This review article highlighted the role of vitamin D in managing vitamin D deficiency and its role as a supplement in the management of respiratory tract infections, especially COVID-19. This overview can assist physicians in optimising healthcare by optimised dosing recommendations and indications.


Assuntos
COVID-19 , Colestanos , Humanos , Calcifediol , Ergocalciferóis/uso terapêutico , Pandemias , Vitamina D/uso terapêutico , Vitaminas/uso terapêutico , Suplementos Nutricionais , COVID-19/epidemiologia , COVID-19/prevenção & controle
10.
Anal Methods ; 15(44): 6009-6014, 2023 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-37927098

RESUMO

Vitamin D (VD) metabolites are involved in a variety of important metabolic processes and physiological effects in organisms. Profiling of VD metabolites favors a deep understanding of the physiological role of VD. However, VD metabolites are difficult to detect due to their high chemical structural rigidity, structural similarity, and low sensitivities under liquid chromatography-tandem mass spectrometry (LC-MS). Herein, we present a chemical derivatization assisted LC-MS/MS strategy for the detection of VDs, in which 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) is employed to derivatize the conjugated diene of VD metabolites and provides sensitizing reporters for MS detection. After PTAD derivatization, the sensitivities of seven VD metabolites increased by 24-276 folds, with the limits of detection ranging from 3 to 20 pg mL-1. Using this method, we achieved a sensitive and accurate quantification of 7 VD metabolites (vitamin D2, vitamin D3, 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, 1,25-dihydroxyvitamin D2, 1,25-dihydroxyvitamin D3, and 1,24,25-trihydroxyvitamin D3) of the VD metabolic pathway in different trace biological samples, including human serum, mouse tissues (namely liver, kidney, lung, and spleen), and cells. We believe that the present method can provide a promising tool for an in-depth analysis of VD metabolism.


Assuntos
Espectrometria de Massas em Tandem , Vitamina D , Humanos , Camundongos , Animais , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Vitamina D/análise , Calcifediol/análise , Ergocalciferóis
11.
Clin Cancer Res ; 29(23): 4733-4739, 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-37801295

RESUMO

PURPOSE: Vitamin D analogues remodel the desmoplastic stroma, and improve vascularity and efficacy of chemotherapy in preclinical pancreas cancer models. PATIENTS AND METHODS: We conducted a pilot study to evaluate the safety and preliminary efficacy of the vitamin D analogue paricalcitol in combination with nanoliposomal irinotecan (Nal-iri) plus 5-fluorouracil/leucovorin (5-FU/LV) in patients with advanced pancreatic cancer who had progressed on gemcitabine-based therapy. Two dose levels (DL) of paricalcitol were tested: fixed dose weekly (75 mcg, DL1) and weight-based weekly (7 mcg/kg, /DL2). The primary endpoint was safety, and secondary endpoints included overall response rate, progression-free survival (PFS), and overall survival (OS). Correlative objectives aimed to identify molecular predictors of response and alterations in the tumor stroma. RESULTS: Twenty patients (10 each in DL1 and DL2) enrolled between March 2019 and May 2021. No grade 3/4 adverse events related to paricalcitol were observed. The most common toxicities were nausea, diarrhea and fatigue, which were similar in both cohorts. Three patients discontinued study after one cycle and were not radiographically evaluable. Of the remaining 17 evaluable patients, 2 had partial response and 12 had stable disease. The median PFS for response-evaluable patients in DL1 was 4.14 months, for DL2 was 4.83 months. Intent-to-treat median OS was 6.15 and 6.66 months for DL1 and DL2, respectively. Correlative studies showed increased tumor vascularity in posttreatment samples in patients receiving the higher dose of paricalcitol (DL2). CONCLUSIONS: Paricalcitol at 7 mcg/kg/week in combination with Nal-iri/ 5-FU/LV is safely tolerated, may increase tumor vascularity and warrants further investigation.


Assuntos
Gencitabina , Neoplasias Pancreáticas , Humanos , Irinotecano , Projetos Piloto , Fluoruracila , Lipossomos , Neoplasias Pancreáticas/patologia , Ergocalciferóis/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Leucovorina , Neoplasias Pancreáticas
12.
Nutrients ; 15(16)2023 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-37630783

RESUMO

Low vitamin D (VitD) level is a risk factor for preterm birth (PTB), but the results of previous studies remained inconsistent, which may be influenced by the confounding factors and different types of PTB. We performed Mendelian randomization (MR) to uncover the association of 25-hydroxyvitamin D (25(OH)D) with PTB, premature rupture of membranes (PROM), and preterm premature rupture of membranes (PPROM). This study was conducted in Zhoushan Maternal and Child Health Hospital, Zhejiang, from August 2011 to March 2022. Plasma 25(OH)D levels in three trimesters of pregnancy were measured. We conducted an MR analysis utilizing a genetic risk score (GRS) approach, which was based on VitD-associated single-nucleotide polymorphisms. The prospective cohort study included 3923 pregnant women. The prevalence of PTB, PROM, and PPROM were 6.09%, 13.18%, and 1.33%, respectively. Compared to those without vitamin D deficiency (VDD), only vaginally delivering pregnant women with VDD had a 2.69 (1.08-6.68) times risk of PTB. However, MR analysis did not support the association. One-unit higher GRS was not associated with an increased risk of PTB, regardless of the trimesters (OR [95% CI]: 1.01 [0.93-1.10], 1.06 [0.96-1.18], and 0.95 [0.82-1.10], respectively). When further taking PROM and PPROM as the outcomes, the MR analysis also showed no consistent evidence of a causal effect of VitD levels on the risk of them. Our MR analyses did not support a causal effect of 25(OH)D concentrations in the three trimesters on PTB, PROM, and PPROM.


Assuntos
Análise da Randomização Mendeliana , Nascimento Prematuro , Recém-Nascido , Gravidez , Criança , Feminino , Humanos , Nascimento Prematuro/epidemiologia , Nascimento Prematuro/genética , Estudos Prospectivos , Vitamina D , Calcifediol , Vitaminas , Ergocalciferóis
13.
J Steroid Biochem Mol Biol ; 233: 106367, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37517743

RESUMO

Many assays are currently being developed to measure the levels of vitamin D metabolites in various samples (such as blood, urine, and saliva). This study focused on the measurement of vitamin D metabolites in serum and urine using the NLucVDR assay system, which consists of a split-type nanoluciferase and ligand-binding domain (LBD) of the human vitamin D receptor. Blood and urine samples were collected from 23 participants to validate the NLucVDR assay. The 25(OH)D3 levels in the serum and urine determined by the NLucVDR assay showed good correlations with those determined by standard analytical methods (ECLIA for serum and LC-MS/MS for urine), with correlation coefficients of 0.923 and 0.844 for serum and urine samples, respectively. In the case of serum samples, 25(OH)D3 levels determined by the NLucVDR assay were in good agreement with those determined by ECLIA. Therefore, the NLucVDR assay is a useful tool for measuring serum 25(OH)D3 levels. The contribution of each vitamin D metabolite to the luminescence intensity obtained during the NLucVDR assay depends on its concentration and affinity for NLucVDR. Thus, the contribution of 25(OH)D3 in serum appears to be much higher than that of the other metabolites. In contrast, the 25(OH)D3 levels in the urine determined by the NLucVDR assay were more than 20-fold higher than those determined by a standard analytical method (LC-MS/MS), suggesting that some vitamin D metabolite(s) in the urine remarkably increased the luminescence intensity of the NLucVDR assay. Notably, the 25(OH)D3 concentration in the urine determined by the NLucVDR assay and the serum 25(OH)D3 concentration determined by standard analytical methods showed a significant positive correlation (r = 0.568). These results suggest that the analysis of a small amount of urine using the NLucVDR assay may be useful for predicting the serum 25(OH)D3 levels.


Assuntos
Receptores de Calcitriol , Espectrometria de Massas em Tandem , Vitamina D , Humanos , Cromatografia Líquida/métodos , Ergocalciferóis , Ligantes , Espectrometria de Massas em Tandem/métodos , Vitamina D/análise , Vitamina D/metabolismo , Vitaminas
14.
J Steroid Biochem Mol Biol ; 233: 106368, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37495192

RESUMO

Vitamin D is found in two forms in humans, D3 produced in the skin and D2 solely from the diet. Both 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) are oxidised and inactivated by CYP24A1, a tightly regulated mitochondrial enzyme that controls serum levels of these secosteroids. The pathways of oxidation of 25(OH)D2 and 1,25(OH)2D2, particularly 25(OH)D2, by human CYP24A1 are not well characterized. The aim of this study was to further elucidate these pathways, and to compare the kinetics of metabolism of 25(OH)D2 and 1,25(OH)2D2 with their vitamin D3 counterparts. We used expressed and partially purified human CYP24A1 with substrates dissolved in the membrane of phospholipid vesicles, to mimic the inner mitochondrial membrane. We found that the major pathways for side chain oxidation of 25(OH)D2 and 1,25(OH)2D2 were identical and that predominant intermediates of 25(OH)D2 metabolism could be converted to the corresponding intermediates in the pathway of 1,25(OH)2D2 oxidation by 1α-hydroxylation by CYP27B1. The initial steps in the CYP24A1-mediated oxidation involved hydroxylation at the C24R position, and another unknown position where the alcohol was oxidised to an aldehyde. The 24R-hydroxylation was followed by hydroxylation at C26 or C28, or cleavage between C24 and C25 to produce the 24-oxo-25,26,27-trinor derivative. All of these products were further oxidised, with 24-oxo-25,26,27-trinor-1(OH)D2 giving a product tentatively identified as 24-oxo-25,26,27-trinor-1,28(OH)2D2. The catalytic efficiency (kcat/Km) of CYP24A1 for initial 25(OH)D2 hydroxylation was similar to that for 25(OH)D3, indicating that they have similar rates of inactivation at low substrate concentrations, supporting that vitamins D2 and D3 are equally effective in maintaining serum 25(OH)D concentrations. In contrast, the kcat/Km value for 1,25(OH)2D3 was almost double that for 1,25(OH)2D2 indicating a lower rate of inactivation of 1,25(OH)2D2 at a low substrate concentration, suggesting that it has increased metabolic stability in vivo.


Assuntos
Vitamina D , Humanos , Calcifediol/metabolismo , Colecalciferol/metabolismo , Ergocalciferóis , Vitamina D/metabolismo , Vitamina D3 24-Hidroxilase/genética , Vitamina D3 24-Hidroxilase/metabolismo
15.
J Steroid Biochem Mol Biol ; 233: 106370, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37499840

RESUMO

Lumisterol2 (L2) is a photoproduct of UVB action on the fungal membrane sterol, ergosterol. Like vitamin D2, it is present in edible mushrooms, especially after UV irradiation. Lumisterol3 is similarly produced in human skin from 7-dehydrocholesterol by UVB and can be converted to hydroxy-metabolites by CYP27A1 and CYP11A1. These products are biologically active on human cells with actions that include photoprotection and inhibition of proliferation. The aim of this study was to test the ability of CYP11A1 and CYP27A1 to metabolise L2. Purified CYP27A1 was found to efficiently metabolise L2 to three major products and several minor products, whilst CYP11A1 did not act appreciably on L2. The three major products of CYP27A1 action on L2 were identified by mass spectrometry and NMR as 24-hydroxyL2, 27-hydroxyL2 and 28-hydroxyL2. Minor products included two dihydroxy L2 species, one which was identified as 24,27(OH)2L2, and another metabolite with one oxo and one hydroxyl group added. A comparison on the kinetics of the metabolism of L2 by CYP27A1 with that of the structurally similar compounds, L3 and ergosterol, was carried out with substrates incorporated into phospholipid vesicles. CYP27A1 displayed a 12-fold lower Km with L2 as substrate compared to L3 and a 5-fold lower turnover number (kcat), resulting in a 2.2 fold higher catalytic efficiency (kcat/Km) for L2 metabolism. L2 was a much better substrate for CYP27A1 than its precursor, ergosterol, with a catalytic efficiency 18-fold higher. The major CYP27A1-derived hydroxy-L2 products, 24-hydroxyL2, 27-hydroxyL2 and 28-hydroxyL2, inhibited the proliferation of melanoma and epidermoid cancer cell lines. In conclusion, this study shows that L2 is not metabolized appreciably by CYP11A1, but it is a good substrate for CYP27A1 which hydroxylates its side chain to produce 3 major products that display anti-proliferative activity on skin-cancer cell lines.


Assuntos
Enzima de Clivagem da Cadeia Lateral do Colesterol , Ergosterol , Humanos , Ergosterol/metabolismo , Enzima de Clivagem da Cadeia Lateral do Colesterol/metabolismo , Hidroxilação , Espectrometria de Massas , Ergocalciferóis , Colestanotriol 26-Mono-Oxigenase/metabolismo
16.
J Bone Miner Res ; 38(9): 1312-1321, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37409797

RESUMO

In a 36-month randomized controlled trial examining the effect of high-dose vitamin D3 on radial and tibial total bone mineral density (TtBMD), measured by high-resolution peripheral quantitative tomography (HR-pQCT), participants (311 healthy males and females aged 55-70 years with dual-energy X-ray absorptiometry T-scores > -2.5 without vitamin D deficiency) were randomized to receive 400 IU (N = 109), 4000 IU (N = 100), or 10,000 IU (N = 102) daily. Participants had HR-pQCT radius and tibia scans and blood sampling at baseline, 6, 12, 24, and 36 months. This secondary analysis examined the effect of vitamin D dose on plasma measurements of the vitamin D metabolome by liquid chromatography-tandem mass spectrometry (LC-MS/MS), exploring whether the observed decline in TtBMD was associated with changes in four key metabolites [25-(OH)D3 ; 24,25-(OH)2 D3 ; 1,25-(OH)2 D3 ; and 1,24,25-(OH)3 D3 ]. The relationship between peak values in vitamin D metabolites and changes in TtBMD over 36 months was assessed using linear regression, controlling for sex. Increasing vitamin D dose was associated with a marked increase in 25-(OH)D3 , 24,25-(OH)2 D3 and 1,24,25-(OH)3 D3 , but no dose-related change in plasma 1,25-(OH)2 D3 was observed. There was a significant negative slope for radius TtBMD and 1,24,25-(OH)3 D3 (-0.05, 95% confidence interval [CI] -0.08, -0.03, p < 0.001) after controlling for sex. A significant interaction between TtBMD and sex was seen for 25-(OH)D3 (female: -0.01, 95% CI -0.12, -0.07; male: -0.04, 95% CI -0.06, -0.01, p = 0.001) and 24,25-(OH)2 D3 (female: -0.75, 95% CI -0.98, -0.52; male: -0.35, 95% CI -0.59, -0.11, p < 0.001). For the tibia there was a significant negative slope for 25-(OH)D3 (-0.03, 95% CI -0.05, -0.01, p < 0.001), 24,25-(OH)2 D3 (-0.30, 95% CI -0.44, -0.16, p < 0.001), and 1,24,25-(OH)3 D3 (-0.03, 95% CI -0.05, -0.01, p = 0.01) after controlling for sex. These results suggest vitamin D metabolites other than 1,25-(OH)2 D3 may be responsible for the bone loss seen in the Calgary Vitamin D Study. Although plasma 1,25-(OH)2 D3 did not change with vitamin D dose, it is possible rapid catabolism to 1,24,25-(OH)3 D3 prevented the detection of a dose-related rise in plasma 1,25-(OH)2 D3 . © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).


Assuntos
Doenças Ósseas Metabólicas , Vitamina D , Masculino , Feminino , Humanos , Cromatografia Líquida , Espectrometria de Massas em Tandem , Colecalciferol/farmacologia , Ergocalciferóis , Metaboloma , Suplementos Nutricionais
17.
J Zoo Wildl Med ; 54(2): 219-230, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37428684

RESUMO

Vitamin D supplementation may pose a significant health risk in species where levels of deficiency, sufficiency, and toxicity have not been clearly established, and species-specific research on vitamin D supplementation should be performed. This study documented the effect of vitamin D supplementation on serum vitamin D metabolites and other analytes of Ca homeostasis in Asian elephants (Elephas maximus). Six adult Asian elephants received PO supplementation with cholecalciferol at 300 IU/kg of body weight (BW) once a week for 24 wk. Serum was analyzed every 4 wk for 25-hydroxyvitamin D2/D3 [25(OH)D]; 24,25-dihydroxyvitamin D2/D3 [24,25(OH)2D]; 1,25-dihydroxyvitamin D [1,25(OH)2D]; parathyroid hormone (PTH); total Ca; ionized Ca (iCa); P; and Mg. After the supplement was discontinued, serum 25(OH)D2/D3 was measured every 4 wk until levels returned to baseline. At the start of the study, the average serum 25(OH)D3 was nondetectable (<1.5 ng/ml). With cholecalciferol supplementation, 25(OH)D3 increased at an average rate of 2.26 ng/ml per month and reached an average concentration of 12.9 ± 3.46 ng/ml at 24 wk. Both 24,25(OH)2D3 and 1,25(OH)2D increased over time with supplementation from an average of <1.5 to 12.9 ng/ml and from 9.67 to 36.4 pg/ml, respectively. PTH, iCa, Ca, P, and Mg remained within reported normal ranges throughout supplementation. After the supplement was discontinued, serum 25(OH)D3 demonstrated a slow decline to baseline, taking an average of 48 wk. Elephants demonstrated significant individual variation in response to supplementation and subsequent return to baseline. Supplementation of Asian elephants with a weekly dose of 300 IU/kg BW cholecalciferol for 24 wk appears to be effective and safe. Additional clinical studies would be necessary to investigate the safety of other routes of administration, dosages, and duration of vitamin D supplementation, as well as associated health benefits.


Assuntos
Colecalciferol , Elefantes , Animais , Elefantes/metabolismo , Vitamina D , Ergocalciferóis , Hormônio Paratireóideo , Suplementos Nutricionais
18.
J Am Heart Assoc ; 12(14): e028561, 2023 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-37421259

RESUMO

Background The ratio of 24,25-dihydroxyvitamin D3/25-hydroxyvitamin D3 (vitamin D metabolite ratio [VDMR]) may reflect functional vitamin D activity. We examined associations of the VDMR, 25-hydroxyvitamin D (25[OH]D), and 1,25-dihydroxyvitamin D (1,25[OH]2D) with cardiovascular disease (CVD) in patients with chronic kidney disease. Methods and Results This study included longitudinal and cross-sectional analyses of 1786 participants from the CRIC (Chronic Renal Insufficiency Cohort) Study. Serum 24,25-dihydroxyvitamin D3, 25(OH)D, and 1,25(OH)2D were measured by liquid chromatography-tandem mass spectrometry 1 year after enrollment. The primary outcome was composite CVD (heart failure, myocardial infarction, stroke, and peripheral arterial disease). We used Cox regression with regression-calibrated weights to test associations of the VDMR, 25(OH)D, and 1,25(OH)2D with incident CVD. We examined cross-sectional associations of these metabolites with left ventricular mass index using linear regression. Analytic models adjusted for demographics, comorbidity, medications, estimated glomerular filtration rate, and proteinuria. The cohort was 42% non-Hispanic White race and ethnicity, 42% non-Hispanic Black race and ethnicity, and 12% Hispanic ethnicity. Mean age was 59 years, and 43% were women. Among 1066 participants without prevalent CVD, there were 298 composite first CVD events over a mean follow-up of 8.6 years. Lower VDMR and 1,25(OH)2D were associated with incident CVD before, but not after, adjustment for estimated glomerular filtration rate and proteinuria (hazard ratio, 1.11 per 1 SD lower VDMR [95% CI, 0.95-1.31]). Only 25(OH)D was associated with left ventricular mass index after full covariate adjustment (0.6 g/m2.7 per 10 ng/mL lower [95% CI, 0.0-1.3]). Conclusions Despite modest associations of 25(OH)D with left ventricular mass index, 25(OH)D, the VDMR, and 1,25(OH)2D were not associated with incident CVD in chronic kidney disease.


Assuntos
Doenças Cardiovasculares , Insuficiência Renal Crônica , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Estudos Transversais , Vitamina D , Ergocalciferóis , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Vitaminas , Proteinúria , Fatores de Risco
19.
BMC Pediatr ; 23(1): 313, 2023 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-37344793

RESUMO

BACKGROUND: Vitamin D deficiency in patients with cholestasis is due to impaired intestinal vitamin D absorption, which results from decreased intestinal bile acid concentration. Patients with cholestasis usually do not achieve optimal vitamin D status when a treatment regimen for children without cholestasis is used. However, data on high-dose vitamin D treatment in patients with cholestasis are limited. METHODS: This study is a prospective study that included pediatric patients with cholestasis (serum direct bilirubin > 1 mg/dL) who had vitamin D deficiency (serum 25-hydroxyvitamin D, 25-OHD, < 20 ng/mL). In Phase 1, single-day oral loading of 300,000 IU (or 600,000 IU if weight ≥ 20 kg) of vitamin D2 was administered, followed by an additional loading if serum 25-OHD < 30 ng/mL, and 4-week continuation of treatment using a vitamin D2 dose calculated based on the increment of 25-OHD after first loading. In Phase 2, oral vitamin D2 (200,000 IU/day) was administered for 12 days, followed by 400,000 IU/day of vitamin D2 orally for another 8 weeks if serum 25-OHD < 30 ng/mL. RESULTS: Phase 1: Seven patients were enrolled. Three out of seven patients had a moderate increase in serum 25-OHD after loading (up to 20.3-27.2 ng/mL). These patients had conditions with partially preserved bile flow. The remaining four patients, who had biliary atresia with failed or no Kasai operation, had low increments of serum 25-OHD. Phase 2: Eleven patients were enrolled. Eight out of 11 patients had a moderate increase in serum 25-OHD after 200,000 IU/day of vitamin D2 for 12 days. Serum 25-OHD continued increasing after administering 400,000 IU/day of vitamin D2 for another 8 weeks, with maximal serum 25-OHD of 15.7-22.8 ng/mL. CONCLUSION: Very high doses of vitamin D2 (200,000 and 400,000 IU/day) partly overcame poor intestinal vitamin D absorption and resulted in moderate increases in serum 25-OHD in pediatric patients with cholestasis, particularly when cholestasis was caused by uncorrectable bile duct obstruction.


Assuntos
Colestase , Deficiência de Vitamina D , Humanos , Criança , Estudos Prospectivos , Vitamina D/uso terapêutico , Vitaminas/uso terapêutico , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/tratamento farmacológico , Colestase/tratamento farmacológico , Colestase/etiologia , Ergocalciferóis/uso terapêutico
20.
Nutrients ; 15(12)2023 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-37375660

RESUMO

Vitamin D (VD) deficiency (serum 25(OH)D < 50 nmol/L) affects 27.3% of preschool children in Mexico. The purpose of this study was to assess the effect of vitamin D supplementation at different doses on serum 25(OH)D concentrations in preschool children. In a randomized control trial, 222 children 12-30 months old were randomly assigned to one of four treatment groups: (1) Vitamin D2 (Ergocalciferol) 400 IU/day (n = 56); (2) Vitamin D2 (Ergocalciferol) 800 IU/day (n = 55); (3) Vitamin D3 (Cholecalciferol) 1000 IU/day (n = 56); or (4) multiple micronutrients (MM) non-VD (n = 55). Supplements were given five days/wk for three months. Serum 25(OH)D was measured at baseline and after three months. At baseline, mean serum 25(OH)D was 58.9 ± 12.6 nmol/L and 23.4% were VD-deficient. There was a statistically significant increase in serum concentrations of 25(OH)D (range across groups: +8.2 to +17.3 nmol/L). Additionally, the prevalence of vitamin D deficiency decreased after three months: for D2 400 IU, -9.0%; for D2 800 IU, -11.0%; for D3 1000 IU, -18.0%; and for MM non-VD, -2.8% (p < 0.05). No adverse effects were observed. VD supplementation for three months was effective for increasing serum 25(OH)D concentrations and for reducing VD deficiency in preschool children. The highest efficacy was observed by giving 1000 IU D3/d.


Assuntos
Colecalciferol , Deficiência de Vitamina D , Pré-Escolar , Humanos , Colecalciferol/uso terapêutico , Vitamina D , Deficiência de Vitamina D/tratamento farmacológico , Suplementos Nutricionais , Ergocalciferóis/uso terapêutico
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